The overall objective of this research program over the proposed grant period is to devise a viable synthetic strategy for the elaboration of milbemycin beta3 and related antibiotics. The milbemycins, isolated from Streptomyces B-41-146 strain, belong to an architecturally interesting class of antileukemic-antibiotic macrolides which have as a central structural element the spiropyranoketal functionality. In addition to their potential as antitumor agents, the milbemycins have remarkable pesticidal activity against mites, rice leaf beetles and tent caterpillars. Significant in the latter regard, the milbemycins show no phytotoxicity thereby enhancing their potential utility as agents for control of insect pests. Subgoals of this research program will be to obtain new information on the reactivity of lactones toward nucleophilic reagents, the stability and conformations of cyclic hemiketals, and the viability and stereochemistry the intramolecular aldol cyclizations. This information will lead to new technology for the synthesis of spiroketal macrolides of biological importance.